Yap5 Protein-regulated Transcription of the TYW1 Gene Protects Yeast from High Iron Toxicity

Li, Liangtao; Jia, Xuan; Ward, Diane M.; Kaplan, Jerry

doi:10.1074/jbc.m111.286666

Cited by 45 publications

(60 citation statements)

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“…Fe/S cluster association induces a conformational change in the dimeric activator domain that likely is of gene regulatory importance. The resulting transcriptional induction of, among other genes, CCC1, encoding a vacuolar divalent metal transporter eventually results in the sequestering of excess iron into the vacuole for detoxification (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Aft1 and Aft2 play a central role in iron-dependent transcription activation of genes encoding components involved in cellular uptake and intracellular distribution of iron (9, 10). Yap5 is involved in the detoxification of excess iron by inducing the transcription of, e.g., CCC1 encoding the only known iron importer into the vacuole, the major metal storage organelle in fungi (11,12). Yap5 belongs to a fungus-specific family of stress response regulators that contains eight members in S. cerevisiae (13-15).…”

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confidence: 99%

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The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

Rietzschel

Pierik

Bill

et al. 2015

Molecular and Cellular Biology

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Iron is an essential, yet at elevated concentrations toxic trace element. To date, the mechanisms of iron sensing by eukaryotic iron-responsive transcription factors are poorly understood. The Saccharomyces cerevisiae transcription factor Yap5, a member of the Yap family of bZIP stress response regulators, administrates the adaptive response to high-iron conditions. Despite the central role of the iron-sensing process for cell viability, the molecule perceived by Yap5 and the underlying regulatory mechanisms are unknown. Here, we show that Yap5 senses high-iron conditions by two Fe/S clusters bound to its activator domain (Yap5-AD). The more stable iron-regulatory Fe/S cluster at the N-terminal cysteine-rich domain (n-CRD) of Yap5 is detected in vivo and in vitro. Iron is a key trace element for virtually all organisms. It functions as an essential cofactor in electron transfer, metabolite biosynthesis, DNA metabolism, and protein translation. Although iron is highly abundant, its bioavailability is low due to its poor solubility under ambient conditions (1, 2). For microbial pathogens, iron acquisition from their host cells is frequently crucial for their virulence. Hence, mutations in microbial genes involved in iron acquisition or utilization are associated with the loss of pathogenicity (3, 4). On the other hand, high intracellular iron levels are both a source and an amplifier of reactive oxygen species and thus highly toxic.Iron acquisition, transport and storage need to be tightly regulated, and disruption or deregulation of iron-related molecules can have significant health consequences. Hence, organisms have developed sophisticated and largely divergent strategies to acquire appropriate cellular iron levels and to avoid iron overloading (5-7). Except for vertebrates, which regulate cellular iron homeostasis mainly on the level of translation by the iron-regulatory proteins IRP1 and IRP2, transcriptional control of iron-responsive gene expression is widespread (7). In a large number of fungi, iron-responsive gene expression is conferred by the interplay of two conserved transcriptional repressors. Of these, the GATAtype transcription factor SreA regulates the expression of genes involved in iron uptake, while the basic leucine zipper (bZIP) transcription factor HapX regulates the iron-responsive expression of genes involved in iron-consuming pathways through interaction with the CCAAT-binding complex CBC (4,8).The model organism Saccharomyces cerevisiae utilizes three iron-responsive transcription factors. Aft1 and Aft2 play a central role in iron-dependent transcription activation of genes encoding components involved in cellular uptake and intracellular distribution of iron (9, 10). Yap5 is involved in the detoxification of excess iron by inducing the transcription of, e.g., CCC1 encoding the only known iron importer into the vacuole, the major metal storage organelle in fungi (11,12). Yap5 belongs to a fungus-specific family of stress response regulators that contains eight members in S. cerevisiae (...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

Rietzschel

Pierik

Bill

et al. 2015

Molecular and Cellular Biology

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“…Iron traffic into and out of vacuoles is also highly regulated, with Yap5 playing the dominant role (30). This iron-sensitive transcription factor is constitutively expressed in the nucleus where it is bound to the promoters of CCC1 (and other genes) to regulate expression (Fig.…”

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confidence: 99%

Mitochondrial Iron-Sulfur Cluster Activity and Cytosolic Iron Regulate Iron Traffic in Saccharomyces cerevisiae

Wofford

Lindahl

2015

Journal of Biological Chemistry

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Background: A mathematical model of iron trafficking and regulation in yeast cells was developed. Results: The model simulated experimental data from the literature fairly well. Conclusion: Both cytosolic iron and an exported product of mitochondrial iron-sulfur cluster activity appear to regulate iron traffic. Significance: The model has some predictive power that can be used to probe the mechanism of mitochondrial iron diseases.

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“…Under the same conditions, FET3 mRNA was increased in the absence of SSQ1. We then assayed the levels of TYW1, another Yap5 target gene (9). In ⌬ccc1 cells, TYW1 mRNA levels were decreased in the absence of SSQ1, YFH1, or ISU1 when compared with ⌬ccc1 cells with unimpaired Fe-S cluster synthesis (Fig.…”

Section: Failure To Induce the Yap5 Transcriptional Response Due To Dmentioning

confidence: 99%

“…Yap5 is constitutively present in the nucleus, where it occupies the promoters of at least three genes (CCC1, TYW1, GRX4) (8 -10). Most notably, CCC1, which encodes the vacuolar iron importer, plays a major role in regulating cytosolic iron concentration (8,9). The activation domain of Yap5 contains 7 cysteines important for iron sensing as mutation of those cysteines reduces transcription.…”

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confidence: 99%

A Role for Iron-Sulfur Clusters in the Regulation of Transcription Factor Yap5-dependent High Iron Transcriptional Responses in Yeast

Li¹,

Ren²,

Bertram

et al. 2012

Journal of Biological Chemistry

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Background: Saccharomyces cerevisiae responds to increased cytosolic iron through changes in the activity of the transcriptional activator Yap5. Results: A genetic screen identified a mutation in SSQ1 that prevented Yap5-dependent transcription. Conclusion: Reduced levels of proteins required for mitochondrial iron-sulfur cluster synthesis prevented Yap5-dependent transcription. Significance: The transcriptional response to low iron or high cytosolic iron is dependent on iron-sulfur clusters.

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Yap5 Protein-regulated Transcription of the TYW1 Gene Protects Yeast from High Iron Toxicity

Cited by 45 publications

References 24 publications

The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

Mitochondrial Iron-Sulfur Cluster Activity and Cytosolic Iron Regulate Iron Traffic in Saccharomyces cerevisiae

A Role for Iron-Sulfur Clusters in the Regulation of Transcription Factor Yap5-dependent High Iron Transcriptional Responses in Yeast

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